1. Field of the Invention
The present invention relates to a method for treating gastrointestinal motility disorders and compounds for use in the method and in particular a method for treating disorders associated with delayed gastric emptying and upper bowel transit.
2. Disclosure Statement
Impaired motility of the alimentary canal can lead to a variety of gastrointestinal diseases and symptoms such as gastroesophageal reflux, reflux esophagitis, diffuse esophageal spasms, gastric stasis, intestinal obstruction, paralytic ileus, abdominal pain, nausea, vomiting and constipation. Disorders associated with delayed gastric emptying can be caused by mechanical obstruction due to increased resistance or functional obstruction due to pump failure.
Functional gastric obstruction may be produced, for example, by certain drugs such as anticholinergics, narcotics and calcium channel blockers; metabolic disorders such as diabetic neuropathy and hypothyroidism; electrolyte imbalance including hypokalemia, hypocalcemia or hypomagnesemia; central or peripheral neurological disorders; inflammation of the stomach due to infective agents or vasculitis; abdominal trauma; severe pain; caloric deprivation such as anorexia nervosa; gastric ulcer; and tachygastria (ectopic gastric pacemaker).
Treatment of these diseases may be undertaken with a variety of motility enhancing (gastroprokinetic) agents such as muscarinic agonists, cholinesterase inhibitors, metoclopramide and domperidone. Available therapy is limited, however, by lack of specificity, potency, and/or side effects. The clinically preferred method of treatment in man is with metoclopramide hydrochloride (Reglan.RTM.) as indicated in Physicians' Desk Reference, pages 1634-1636 (1987). However, metoclopramide has been shown to have both cholinergic and dopamine antagonistic effects. And because metoclopramide crosses the blood-brain barrier it may be associated with side-effects such as sedation and extrapyramidal changes in a large percentage of patients and at higher doses a number of other side-effects have been observed. Hence, there is a need for an agent which will enhance gastrointestinal motility and be devoid of side effects.
Recent reviews on the development of gastrointestinal motility enhancing agents and motility disturbances may be found in J. S. Gidda and I. Monkovic, Annual Reports in Medicinal Chemistry, 20, 117-125 (1985), in R. S. Fisher, Scandinavian J. Gastroenteroloqy, 20 (suppl. 109), 59-68 (1985), and in references cited therein.
There is described in U.S. Pat. No. 4,394,508 issued July 19, 1983 to R. R. Crenshaw and A. A. Algieri a series of thiadiazole oxide compounds which are histamine H.sub.2 -receptor antagonists and inhibit gastric acid secretion and, therefore, are useful in the treatment of peptic ulcers. There is no disclosure that any of these compounds have motility enhancing properties or use as gastroprokinetic agents. In addition, the three commercially available histamine H.sub.2 -receptor antagonists, cimetidine (Tagamet.RTM.), ranitidine (Zantac.RTM.) and famotidine (Pepcid.RTM.) are not indicated as gastroprokinetic agents [Physicians' Desk Reference, pages 2031-2033 (1988), pages 1028-1029 (1988) and pages 1380-1381 (1988), respectively].
Surprisingly, we have found that certain compounds disclosed in U.S. Pat. No. 4,394,508 are effective gastric motility enhancing agents which may lack the potential side effects associated with the present agents, and therefore, are useful in the treatment of gastrointestinal motility disorders.